Dosage form containing (s)-pantoprazole as active ingredient

ABSTRACT

Dosage forms for oral administration of the magnesium salt of (S)-pantoprazole are described.

TECHNICAL FIELD

The present invention relates to the field of pharmaceutical technologyand describes a dosage form for oral administration of the magnesiumsalt of (S)-pantoprazole. The invention additionally relates toprocesses for producing the dosage form.

PRIOR ART

It is generally known to coat peroral administration forms, e.g. tabletsor pellets which contain an acid-labile active compound, with an entericcoating which, after passage through the stomach, rapidly dissolves inthe alkaline medium of the intestine. Examples of such acid-labileactive compounds are acid-labile proton pump inhibitors (H⁺K⁺ ATPaseinhibitors), in particular pyridin-2-ylmethylsulfinyl-1H-benzimidazoles,such as are disclosed, for example, in EP-A-0 005 129, EP-A-0 166 287,EP-A-0 174 726 and EP-A-0 268 956. On account of their H⁺/K⁺ATPase-inhibiting action, these are of importance in the therapy ofdiseases, which are due to increased gastric acid secretion. Examples ofactive compounds from this group which are commercially available are5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: omeprazole),5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: pantoprazole),2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: lansoprazole) and2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]-methylsulfinyl}-1H-benzimidazole(INN: rabeprazole).

Because of their strong tendency to decompose in a neutral and, inparticular, in an acidic environment, where strongly coloreddecomposition products are also formed, for oral preparations it is alsonecessary in this case to protect the active compounds from the actionof acids. In the case of the strongly acid-labilepyridin-2-ylmethylsulfinyl-1H-benzimidazoles, it is moreover necessaryto process these in the tablet core or in pellets in the form of theiralkaline salts, for example as sodium salts, or together with alkalinesubstances. Since the substances suitable for enteric coatings are thosehaving free carboxyl groups, the problem results that the entericcoating is partly dissolved or even dissolved from inside because of thealkaline medium in the interior and the free carboxyl groups promote thedecomposition of the active compounds. It may therefore be necessary toprovide an isolating intermediate layer (subcoating) between the entericcoating and the alkaline tablet core or pellet. It is proposed in EP-A-0244 380 to coat cores which contain the active compound together withalkaline compounds or as an alkaline salt with at least one layer ofnonacidic, inert pharmaceutically acceptable substances, which aresoluble in water or rapidly decompose in water, before the enteric layeris applied. The intermediate layer or intermediate layers act aspH-buffering zones in which the hydrogen ions diffusing in from outsidecan react with the hydroxyl ions diffusing from the alkaline core. Inorder to increase the buffer capacity of the intermediate layer, it isproposed to incorporate buffer substances into the intermediatelayer(s). In practice, it is possible by this process to obtain somewhatstable preparations. However, relatively thick intermediate layers areneeded in order to avoid the unsightly discolorations occurring even inthe case of only slight decomposition. Moreover, a considerable effortis to be made in the preparation to avoid traces of moisture.

In EP-A-0 519 365, a formulation on the principle of the alkaline corecoated with a water-soluble intermediate layer and an enteric coating isproposed for the active compound pantoprazole, in which improvedstability is achieved by use of polyvinylpyrrolidone and/orhydroxypropylmethylcellulose as binders for the alkaline core. It isdisclosed that as binder a polyvinylpyrrolindone of higher molecularweight is used.

EP-A-0 342 522 discloses a formulation for acid-sensitive benzimidazolesin which, between the alkaline core and the enteric coating, anintermediate layer is located which is composed of only slightlywater-soluble film-forming material, such as ethylcellulose andpolyvinyl acetate, and a slightly water-soluble finely granularinorganic or organic material suspended therein, such as, for example,magnesium oxide, silicon oxide or sucrose fatty acid esters.

EP-A-0 277 741 describes spherical granules having a core which iscoated with spray powder, which contains low-substitutedhydroxypropylcellulose and a benzimidazole compound having anti-ulceractivity. These granules can be coated with an enteric coating agent.

EP-A-1 213 015 discloses an oral pharmaceutical composition with delayedrelease of proton pump inhibitors.

As the abovementioned prior art shows, the production of peroraladministration forms for acid-labile active compounds requirestechnically complicated processes.

For the first time, the international patent application WO92/08716describes a chemical process, which allowspyridin-2-ylmethylsulphinyl-1H-benzimidazoles to be separated into theiroptical antipodes. The compounds mentioned as being prepared in anexemplary manner include inter alia the compounds (+)- and(−)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazole[=(+)- and (−)-pantoprazole]. The international patent applicationWO92/08716 mentions that the optical antipodes of thepyridin-2-ylmethylsulphinyl-1H-benzimidazoles, i.e. the (+)- and(−)-enantiomers or the (R)- and (S)-enantiomers, are used as activecompounds in medicaments for the treatment of gastrointestinaldisorders. For the mode of application and the dosage of the activecompounds, reference is made inter alia to the European patent 166 287.

The international patent applications WO94/24867 and WO94/25028 claimthe use of the compounds (−)- and (+)-pantoprazole for treating gastricdisorders in humans. Each stereoisomer is said to have medicaladvantages compared to the respective other stereoisomers. Thedescriptions also mention a number of different possible salts of thestereoisomers, and particular preference is given to the sodium salt.

The International Patent Application WO97/41114 describes a specificprocess for the preparation of magnesium salts ofpyridin-2-ylmethylsulfinyl-1H-benzimidazoles. Inter alia, thepreparation of the magnesium salt of pantoprazole is also described byway of example. According to the analysis data indicated, the saltprepared is pantoprazole magnesium in anhydrous form.

International Patent Application WO00/10995 describes the dihydrate ofthe magnesium salt of pantoprazole. It is disclosed that the dihydrateof the magnesium salt of pantoprazole has inter alia improved stabilityproperties as in comparison to pantoprazole itself or to pantoprazolesodium sesquihydrate.

International Patent Application WO04/013126 is related to(−)-pantoprazole magnesium and its hydrates and to medicamentscomprising these compounds.

DESCRIPTION OF THE INVENTION

It is an object of the present invention to provide a dosage form fororal administration of (S)-pantoprazole magnesium salt, which dosageform can be produced without great technical complexity, which takesaccount of the acid lability of pantoprazole and which makes availablethe pantoprazole magnesium salt effectively for the body in such a waythat an optimal active ingredient profile and thus action profile isachieved.

Surprisingly, it has been found now that (S)-pantoprazole magnesium oraldosage forms have unexpected release profiles of active ingredient andclinical advantages.

In one aspect the invention therefore relates to an oral pharmaceuticaldosage form comprising (S)-pantoprazole magnesium together withpharmaceutically acceptable excipients.

Surprisingly it has also been found now that oral dosage forms for(S)-pantoprazole magnesium salt comprising low molecular weightpolyvinylpyrrolidone as excipient show stability and a distinctlyimproved release profile for the active ingredient as compared to oraldosage forms for pantoprazole magnesium salt known from the art.

The invention therefore also relates to a dosage form for oraladministration of (S)-pantoprazole magnesium salt comprising atherapeutically effective amount of the (S)-pantoprazole magnesium salttogether with low molecular weight polyvinylpyrrolidone and one or moreother suitable pharmaceutical excipients.

A dosage form means, in particular, a medicinal dosage form such as atablet, a coated tablet, a multiparticulate form such as pellets orpellets and microtablets in a capsule or a multiple unit tableted dosageform (such as disclosed in WO 96/01623), with the dosage formadvantageously being designed so that the pantoprazole magnesium salt isreleased, or made available effectively for the body, in such a way thatan optimal active ingredient profile, and thus action profile, isachieved. Unit in connection with the multiple unit tableted dosage formrefers to an individual unit containing the pantoprazole magnesium salt,which individual unit can be a small bead, particle, granule or pellet,in connection with the invention also referred to as pellet. Suitabledosage forms are for example disclosed in EP-A-0 519 365, EP-A-0 244380, EP-A-1 213 015, EP-A-1 105 105, EP-A-1 037 634, EP-A-1 187 601 andEP-A-1 341 528.

The oral dosage form of the invention is preferably a dosage form withmodified release of the active ingredient, in particular with delayedrelease of active ingredient. Particularly preferred is an entericcoated dosage form, comprising at least one enteric coating layer whichis stable and does not release the active ingredient under acidicconditions but rapidly dissolves in neutral conditions and in particularin the alkaline medium of the intestine. In a further preferredembodiment the dosage form according to the invention in addition to theenteric coating layer contains one or more intermediate layers(subcoating layers). In another embodiment the dosage form according tothe invention comprises at least one enteric coating layer but does notcontain an intermediate layer.

Pantoprazole is the INN (International Nonproprietary Name) for thecompound5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole.The magnesium salt of pantoprazole is the chemical compound magnesiumbis[5-[difluoromethoxy]-2-[[3,4-dimethoxy-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazolide].The magnesium salt of (S)-pantoprazole [hereinafter also referred to as(−)-panto-prazole] and its hydrates in connection with the inventionrefers to the compound magnesium(−)-bis{[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazolide}including hydrates thereof. Here, particular emphasis is given tohydrates, which, after drying under reduced pressure at 50° C., have awater content of from 4.0 to 6.7% (by weight), in particular from 4.0 to5.5%. Particular preference is given to the hydrate form which has awater content of from 4.0 to 5.0%, in particular from 4.2 to 4.4%, whichcorresponds to a dihydrate. The magnesium salt and its hydrates havehighly surprising stability properties, making it a particularlysuitable candidate for use in solid or oral dosage forms. Compared tothe sodium salt of (−)-pantoprazole, it has considerably improvedstability properties. Thus, for example, (−)-pantoprazole magnesiumdihydrate is, at 70° C., completely stable for one week and showsvirtually no discolouration or decomposition, whereas over the sameperiod of time and under identical conditions, the colour of the hydrateof (−)-pantoprazole sodium changes to brown, with formation ofconsiderable amounts of decomposition products. Furthermore, the(−)-pantoprazole magnesium dihydrate is a non-hygroscopic salt having adefined water content, which corresponds to that of the dihydrate, this(−)-pantoprazole sodium absorbs water depending on drying conditions andatmospheric humidity, and, correspondingly, its water content variesfrom 2 to 12%. This absorption of water is reversible, so that it isdifficult to adjust an exact water content. Compared to the racemicpantoprazole magnesium dihydrate, the (−)-pantoprazole magnesiumdihydrate has, surprisingly, better wettability, a considerably higherdissolution rate and, at pH 7.4, better solubility.

The hydrates of (−)-pantoprazole magnesium are prepared in a mannerknown per se by reacting (−)-pantoprazole with a magnesium base, forexample a magnesium alkoxide, or from a readily soluble (−)-pantoprazolesalt (for example (−)-pantoprazole sodium) using a magnesium salt inwater or in mixtures of water with polar organic solvents (for examplealcohols, preferably methanol, ethanol or isopropanol, or ketones,preferably acetone).

Magnesium salts suitable for use in the process are, for example,magnesium chloride, magnesium bromide, magnesium fluoride, magnesiumiodide, magnesium formate, magnesium acetate, magnesium propionate,magnesium gluconate or magnesium carbonate. It is also possible to reactmagnesium alkoxides (for example magnesium methoxide, magnesiumethoxide, magnesium (iso)propoxide, magnesium butoxide, magnesiumhexoxide or magnesium phenoxide) in aqueous medium with (−)-pantoprazoleor (−)-pantoprazole sodium.

Because of a great tendency to decompose in a neutral and, inparticular, acidic environment, which also results in highly coloreddecomposition products, for oral compositions, it is preferred on theone hand to keep the magnesium salt of pantoprazole in an alkalineenvironment and, on the other hand, to protect it from exposure toacids. It is generally known to coat tablets or pellets, which containan acid-labile active ingredient with an enteric coating which, afterpassage through the stomach, rapidly dissolves in the alkaline medium inthe intestine. In the case of pantoprazole, which is very acid-labile,it is preferred to process it in the tablet core or in pellets in theform of its alkaline salts, and preferably together with alkalinesubstances. Since the substances suitable for enteric coatings containfree carboxyl groups, a problem arises when the enteric coating ispartly or even completely dissolved from the inside because of thealkaline medium in the interior, and the free carboxyl groups promotedecomposition of the active ingredients. It is therefore preferred toprovide a sealing intermediate layer (subcoating) between the entericcoating and an alkaline tablet or pellet core. EP-A 0244380 proposes tocoat cores, which contain the active ingredient together with alkalinecompounds or as alkaline salt with at least one layer, which is solublein water or rapidly disintegrates in water, of nonacidic, inertpharmaceutically-acceptable substance before the enteric layer isapplied.

The intermediate layer or intermediate layers act as pH-buffering zonesin which hydrogen ions, which diffuse in from the outside, are able toreact with the hydroxyl ions which diffuse out of the alkaline core. Inorder to increase the buffer capacity of the intermediate layer, it isproposed to incorporate buffer substance into the intermediate layer(s).It is possible in practice by this method to obtain rather stablecompositions.

The invention therefore also relates to an oral dosage form in pellet ortablet form for magnesium salt of (S)-pantoprazole comprising atherapeutically effective amount of the magnesium salt of(S)-pantoprazole together with one or more other pharmaceuticalexcipients in a pellet or tablet core, at least one subcoating(intermediate layer) and an outer enteric layer which is soluble in thesmall intestine.

The invention further relates to an oral dosage form in pellet or tabletform for magnesium salt of (S)-pantoprazole comprising a therapeuticallyeffective amount of the magnesium salt of (S)-pantoprazole together withone or more other pharmaceutical excipients in an alkaline pellet ortablet core, at least one subcoating (intermediate layer) and an outerenteric layer which is soluble in the small intestine.

In another embodiment the invention also relates to an oral dosage formin pellet or tablet form for magnesium salt of (S)-pantoprazolecomprising a therapeutically effective amount of the magnesium salt of(S)-pantoprazole together with polyvinypyrrolidon and optionally one ormore other pharmaceutical excipients in an alkaline pellet or tabletcore, at least one subcoating (intermediate layer) and an outer entericlayer which is soluble in the small intestine.

In another embodiment the invention also relates to an oral dosage formin pellet or tablet form for magnesium salt of (S)-pantoprazolecomprising a therapeutically effective amount of the magnesium salt of(S)-pantoprazole together with PVP90 and optionally one or more otherpharmaceutical excipients in an alkaline pellet or tablet core, at leastone subcoating (intermediate layer) and an outer enteric layer which issoluble in the small intestine.

In another embodiment the invention also relates to an oral dosage formin pellet or tablet form for magnesium salt of (S)-pantoprazolecomprising a therapeutically effective amount of the magnesium salt of(S)-pantoprazole together with low molecular weight polyvinypyrrolidonand optionally one or more other pharmaceutical excipients in analkaline pellet or tablet core, at least one subcoating (intermediatelayer) and an outer enteric layer which is soluble in the smallintestine.

In one embodiment of the invention the oral dosage form is a multipleunit tableted dosage form, with individual enteric coating layered unitscontaining (S)-pantoprazole magnesium salt and optionally otherexcipients.

Further suitable pharmaceutical excipients, which may be used in thedosage form according to the invention are pharmaceutical excipientssuch as fillers, binders, disintegrants or else lubricants and releaseagents. Other suitable excipients, which may be present in the dosageform of the invention are, for example, flavoring substances (such asflavors and sweeteners), buffer substances, preservatives, coloringsubstances (such as iron oxid yellow or red), wetting agents,surfactants (such as sodium laurylsulfate) or else emulsifiers. Flavorsare usually added in a proportion of from 0.05 to 1% by weight. Otherflavoring substances by way of example are acids such as citric acid,sweeteners such as saccharin, aspartame, cyclamate sodium or maltol,which are added according to the desired result.

Suitable binders which can be used for preparing the tablet or pelletcore are polyvinylpyrrolidone (PVP), hydroxypropymethylcellulose,hydroxypropylcellulose, sodium carboxymethylcellulose, gelatine, wherebyPVP is preferred.

In a preferred embodiment the invention also relates to a dosage formfor oral administration of (S)-pantoprazole magnesium salt comprising atherapeutically effective amount of the (S)-pantoprazole magnesium salttogether with polyvinylpyrrolidone (PVP) as a binder and one or moreother suitable pharmaceutical excipients.

The polyvinylpyrrolidone (PVP) employed as binder according to theinvention can be of molecular weight in the range of 2.000-1.500.000. Inone embodiment PVP 90 (average molecular weight about1.000.000-1.500.000) or PVP in the range of from 600 000 to 700 000 canbe mentioned as preferred. In another embodiment of the invention thePVP is a water-soluble PVP with a low average molecular weight and ispreferably used as binder in the dosage form. Low average molecularweight in connection with the invention refers to PVP with an averagemolecular weight below 300 000, preferably below 100 000, particularlypreferably below 70 000, more particularly preferably below 60 000, mostparticularly preferred below 40 000. Examples, which may be mentioned,are Kollidon 12 PF (molecular weight 2 000-3 000), Kollidon 17 PF(molecular weight 7 000-11 000), Kollidon 25 (molecular weight 28 000-34000) and Kollidon 30 (molecular weight 44 000-54 000), whereby Kollidon25 is preferred.

The proportion (in percent by weight based on the finished dosage form)of PVP as a binder (and, where appropriate, additional other binders)may preferably be according to the invention from 0.5 to 15% by weight.The proportion of PVP is preferably from 1 to 5% by weight, particularlypreferably from 1.5 to 3.5% by weight.

Suitable fillers in connection with the invention are mannitol, lactose,starch, cellulose and calcium phosphate, whereby mannitol is preferred.In one embodiment of the invention mannitol is the sole filler used forthe oral dosage forms according to the invention.

For a basic reaction of the pellet or tablet core (=alkaline tablet orpellet core) it is mixed (where required increase in pH is not achievedsimply by using an active-ingredient salt) with an inorganic base.Mention may be made in this connection of, for example, thepharmacologically-suitable (tolerable) alkali-metal,alkaline-earth-metal or earth-metal salts of weak acids and thepharmacologically-suitable hydroxides and oxides of alkaline-earth andearth metals. Sodium carbonate may be mentioned as a base to beemphasized by way of example.

Besides filler and binder, other ancillary substances, in particularlubricants and nonstick agents, and tablet disintegrants, are used inthe manufacture of tablet cores. Examples of lubricants and nonstickagents, which may be mentioned, are higher fatty acids and theiralkali-metal and alkaline-earth-metal salts, such as calcium stearate.Suitable disintegrants are, in particular, chemically inert agents.Tablet disintegrants, which may be mentioned as preferred, arecrosslinked polyvinylpyrrolidone, crosslinked sodiumcarboxymethylcelluloses, sodium starch glycolate and pregelatinizedstarch.

In one embodiment of the invention the oral dosage form according to theinvention is a tablet and comprises as excipients for the tablet coresodium carbonate, mannitol, crospovidone, polyvinylpyrrolidone andcalcium stearate.

In another embodiment of the invention the oral dosage form according tothe invention is in pellet form on the basis of nonpareilles/seeds andthe pellet core comprises starch as excipient. It has been foundsurprisingly that by using starch as excipient in the pellet core (basedon nonpareilles/seeds) the release of the (S)-pantoprazole magnesiumfrom the pellet core is faster and increased as compared to pelletswithout starch in the pellet core. Suitable types of starch, which canbe used in this connection are different types of starch such as cornstarch, potatoe starch, rice starch, wheat starch, preferablypregelatinized starch and in particular pregelatinized corn starch(Starch 1500). In a preferred embodiment according to the invention theamount of pregelatinized starch present in the pellet core is in therange of 0.5-4% per weight (based on the total weight of the pelletcore), particularly preferably in the range of 1-3% per weight.

The pellet core may contain additional excipients such as thosementioned above and those mentioned in connection with tablet cores(e.g. binders, stabilizers, disintegrants, surfactants and wettingagents). Wetting agents in this connection preferably refers tosynthetic tensides (such as polysorbate, spans, brij), sulfate- andsulfonate salts of fatty acids (such as sodium dodecylsulfate),non-ionic tensides (such as poloxamer) and glycerol esters of fattyacids. In a preferred embodiment SDS (sodium dodecylsulfate) is present.Binders, which may be present are for example PVP, HPMC,hydroxypropylcellulose (HPC) and gelatine. Disintegrants, which may bepresent are crosslinked polyvinylpyrrolidone, crosslinked sodiumcarboxymethylcelluloses and sodium starch glycolate.

In another embodiment of the invention the oral dosage form according tothe invention comprises as excipients sodium carbonate, sodiumlaurylsulfate, pregelatinized starch, polyvinylpyrrolidone and sucrose[Pellets]. The oral dosage form is preferably a pellet on the basis ofnonpareilles.

In respect of the intermediate layer(s) to be applied to a pellet coreor tablet core, reference may be made in particular to thosewater-soluble layers such as are usually used before application oflayers which are resistant to gastric juice, or such as are describede.g. in DE-OS 39 01 151. Examples, which may be mentioned of filmpolymers, which can be used for the intermediate layer arehydroxypropyl-methylcellulose and/or polyvinylpyrrolidone, to whichplasticizers (such as, for example, propylene glycol) and/or otheradditives (e.g. talc as an anti-sticking agent) and auxiliaries (e.g.buffers, bases or pigments) can also be added if desired.

In one embodiment of the invention the oral dosage form according to theinvention comprises intermediate layer(s) based onhydroxypropylmethylcellulose as film polymer.

The expert knows, on the basis of his technical knowledge, what outerlayers, which are resistant to gastric juice can be used. Examples ofsuitable polymers for the enteric coating are methacrylic acid/methylmethacrylate copolymer or methacrylic acid/ethyl-acrylate copolymer(Eudragit® L, S, or Eudragit® L30D) or cellulose derivatives, such ascarboxymethylethylcellulose (CMEC, Duodcel®), cellulose acetatephthalate (CAP), cellulose acetate trimellitate (CAT),hydroxypropylmethylcellulose phthalate (HP50, HPSS),hydroxypropylmethylcellulose acetate succinate (HPMCAS) or polyvinylacetate phthalate, to which it is also possible to add, if desired,plasticizer (such as propylene glycol or triethyl citrate) and/or otheradditives and ancillary substances (e.g. buffers, bases, such as,preferably, aluminum hydroxide, or pigments).

In one embodiment of the invention the oral dosage form according to theinvention comprises an enteric coating based on methacrylic acid/methylmethacrylate copolymer or methacrylic acid/ethyl-acrylate copolymer.Eudragit® L30D is particularly preferred (Eudragit® L30D is composed ofmethacrylic acid copolymer (type C) with molecular weight 250.000,sodium dodecylsulfate and polysorbate 80).

The layers are applied in conventional ways using equipment customaryfor these purposes.

The oral dosage form of the invention can be manufactured for example byprocesses known to the skilled worker for producing tablets and pellets(for example as disclosed in the various patent documents relating tooral dosage forms for proton pump inhibitors; the process mentioned inEP-A-0 519 365 or EP-A-0 244 380 may be mentioned by way of example).

Pellets can be obtained as the case may be by application of apreliminary isolation to sucrose starter pellets and subsequentapplication of a 10-20% suspension of the active compound in water withpolyvinylpyrrolidone (PVP) as the binder.

The isolation layer can also be applied, analogously to tablets, usingcorresponding ready-made dispersions (e.g. opadry) in a fluidized bedcoater. The coating with a layer, which is resistant to gastric juice,is carried out by a procedure analogous to that for tablets, usingfluidized bed technology.

In one embodiment of the invention, the pharmaceutical dosage formaccording to the invention is manufactured by producing a suspension ofthe magnesium salt of (S)-pantoprazole in an aqueous solution of PVP andspraying the suspension on a mixture of pharmaceutical excipients toform granules. In a preferred embodiment the PVP is low molecular weightPVP.

In the event of further processing the granules to enteric coatedtablets the granules may be processed together with disintegrant andlubricant components by production processes familiar to the skilledworker to tablets and together with film former, plasticizer andcoloring agent components obtaining the enteric coated tablets accordingto the invention.

Further subject of the invention is therefore a process for productionof an oral dosage form in form of tablets or pellets containing themagnesium salt of (S)-pantoprazole comprising the following steps:

-   (a) production of a suspension of the magnesium salt of    (S)-pantoprazole optionally together with further pharmaceutical    excipients in an aqueous solution of PVP;-   (b) providing a mixture of pharmaceutical excipients and-   (c) granulation of the mixture obtained from (b) with the suspension    obtained from (a).

In a preferred embodiment the PVP is low molecular weight PVP.

In case of dosage forms of the invention in form of tablets the granulesobtained from (c) may be pressed after drying and mixing with lubricantsand where applicable with further pharmaceutical excipients to tabletson a tableting machine and layered to form enteric coated tablets.

In case of dosage forms of the invention in form of multiparticulatesthe granules may be processed into pellets by extrusion andspheronization. Thereby the magnesium salt of (S)-pantoprazole can besuspended in the solution of PVP (a) and then mixed with otherexcipients (O). The mixture can be processed by extrusion/spheronizationusing suitable process equipments. The size of the obtained core pelletsis approximately between 0.2 and 3 mm and preferably between 0.25 and 2mm. In a preferred embodiment the PVP is low molecular weight PVP.

The manufactured extrusion pellets can further be layered withingredients familiar to the skilled worker. The enteric coated pelletsmay be processed after drying by production processes familiar to theskilled worker to give enteric coated pellets which may be filled incapsules after mixing with glidants or pressed to tablets after mixingwith further pharmaceutical excipients.

Alternatively, the suspension obtained from (a) may be sprayed on seeds(e.g. nonpareilles comprising sugar, cellulose or HPMC). The pelletsobtained may be processed after drying by production processes familiarto the skilled worker to give enteric coated pellets which may be filledin capsules after mixing with glidants or pressed into tablets aftermixing with further pharmaceutical excipients.

Particularly preferred the dosage forms of the invention in form oftablets are produced by granulating a mixture of mannitol and insolublePVP with a suspension of the magnesium salt of (S)-pantoprazole, sodiumcarbonate and sodium dodecylsulfate in an aqueous solution of PVP,drying the granules, mixing with lubricant and pressing into tablets ona tableting machine, followed by the coating processes. In oneembodiment the PVP is of low molecular weight.

Particularly preferred the dosage forms of the invention in form ofmultiparticulates based on nonpareilles-technology are produced byspraying a suspension of the magnesium salt of (S)-pantoprazole, sodiumcarbonate and sodium dodecylsulfate in an aqueous solution of PVP onstarter pellets, drying the pellets, layering them with subcoating andenteric coating, mixing with glidants where applicable and filling intocapsules. In a preferred embodiment the PVP is low molecular weight PVP.

In another embodiment which is also a particularly preferred dosageforms of the invention based on nonpareilles-technology the dosage formis produced by spraying a suspension of the magnesium salt of(S)-pantoprazole, sodium carbonate, pregelatinized starch and sodiumdodecylsulfate in an aqueous solution of PVP on starter pellets, dryingthe pellets, layering them with subcoating and enteric coating, mixingwith glidants where applicable and filling into capsules. In a preferredembodiment the PVP is low molecular weight PVP.

Particularly preferred the dosage forms of the invention in form ofextrusion pellets are produced by granulating a mixture ofmicrocrystalline cellulose, sodium carbonate, sodium starch glycolate,sodium carboxymethylcellulose with a suspension of the magnesium salt of(S)-pantoprazole in an aqueous solution of PVP, extruding the wet massand rounding it using a spheronizer or marumerizer. The obtained pelletcores are dryed using a fluid bed dryer or other suitable dryingtechniques. Afterwards the pellets are layered with subcoating andgastric resistant coating, mixed with glidants where applicable andfilled into capsules. In a preferred embodiment the PVP is low molecularweight PVP.

In an other embodiment of the invention the pharmaceutical form of theinvention in form of tablets is produced by granulating a dry mixture ofthe magnesium salt of (S)-pantoprazole and pharmaceutical excipientswith an aqueous solution of PVP, drying the granules and mixing themwith further pharmaceutical excipients where applicable. The granulesmay be compressed into tablets on a tableting machine after mixing withfurther pharmaceutical excipients. Preferably the granulation isproceeded using a fluid bed granulator under convenient conditions. In apreferred embodiment the PVP is low molecular weight PVP.

Subject of the invention is therefore also a process to produce an oraldosage form in form of tablets or multiparticulates containing themagnesium salt of (S)-pantoprazole comprising the following steps:

(a) production of a dry mixture of the magnesium salt of(S)-pantoprazole and pharmaceutical excipients and(b) granulating the mixture obtained from (a) with an aqueous solutionof PVP.

In a preferred embodiment the PVP is low molecular weight PVP.

In case of dosage forms of the invention in form of extrusion pelletsthe aforementioned mixture may be processed into pellets by extrusionand spheronization. Thereby the magnesium salt of (S)-pantoprazole canbe mixed with other excipients (a) and granulated with an aqueoussolution of PVP (b). In a preferred embodiment the PVP is low molecularweight PVP. The mixture can be processed by extrusion/spheronizationusing suitable process equipments. The size of the obtained core pelletsis approximately between 0.2 and 3 mm and preferably between 0.25 and 2mm.

Particularly preferred the dosage forms of the invention in form oftablets are produced by granulating a mixture of the magnesium salt of(S)-pantoprazole, mannit and sodium carbonate and insoluble PVP using anaqueous solution of PVP, drying the granules, mixing with lubricants andpressing into tablets on a tableting machine, followed by the coatingprocesses. In a preferred embodiment the PVP is low molecular weightPVP.

Particularly preferred the dosage forms of the invention in form ofextrusion pellets are produced by granulating a dry mixture ofmicrocrystalline cellulose, sodium carbonate, sodium starch glycolate,sodium carboxymethylcellulose and the magnesium salt of (S)-pantoprazolewith an aqueous solution of PVP, extruding the wet mass and rounding itusing a spheronizer or marumerizer. The obtained pellet cores are dryedusing a fluid bed dryer or other suitable drying techniques, followed bythe above mentioned coating processes. In a preferred embodiment the PVPis low molecular weight PVP.

The production of dosage forms according to the invention is describedby way of example below. The following examples explain the invention inmore detail without restricting it. M.p. denotes melting point, min.denotes minute(s), h denotes hour(s).

EXAMPLES A. Synthesis of Magnesium(−)-bis{[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)-methylsulphinyl]-1H-benzimidazolide}dihydrate

At 20-25° C., 20.2 g (52.7 mmol) of (−)-pantoprazole{(−)-[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazole}are suspended in 200 ml of purified water. A solution of (55.2 mmol)sodium hydroxide in 10 ml of water is added, and the mixture is stirredat 20-30° C. for 30 min. With addition of a filter aid (1 gHyflo-Super-Cel), the turbid solution is filtered. 6.32 g (31.2 mmol) ofmagnesium dichloride hexahydrate in 150 ml of water are then addeddropwise with stirring over a period of 30 min. After a further 30 min.,the precipitated solid is filtered off with suction using a Nutschefilter, stirred with water (2×50 ml) and again filtered off withsuction. Drying under reduced pressure at 50-60° C. gives, in a yield of17.36 g (80%), a hydrate of magnesium(−)-bis{[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazolide}having a water content of 4.5-4.7% as a colourless to beige powder (m.p.158-161° C., with decomposition).

Specific rotation: a_(D) ^(20°)=−114° (c=0.5, measured in methanol)

For recrystallization, 1.88 g of the hydrate are, at 55° C., dissolvedin 6 ml of methanol, and 20 ml of water are added with stirring. Acolourless to beige solid crystallizes out. This gives the titlecompound of m.p. 160-163° C. (with decomposition) having a water contentof 4.3-4.4%.

Alternatively, the title compound can also be prepared fromorganic-aqueous solvent mixtures. To this end, (−)-pantoprazole sodium,or (−)-pantoprazole together with one equivalent of aqueous, for example2N, sodium hydroxide solution, is dissolved in an organic solvent, forexample warm acetone. 0.5 to 0.55 equivalents of a magnesium salt (forexample magnesium chloride hexahydrate), dissolved in water, are addeddropwise, and the mixture is cooled with stirring. The precipitatedsolid is filtered off, washed with the solvent mixture in question anddried at 50° C. under reduced pressure until the weight remainsconstant. This gives the title compound as a colourless to beige powder.

B. Magnesium(−)-bis{[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazolide}dihydrateB.1 (−)-Pantoprazole-Na

36 g of (−)-Pantoprazole are suspended in 180 ml of isobutyl methylketone (MIBK) and 18 ml of 2-propanol and heated to an internaltemperature of 45° C. The suspension is stirred at this temperature for15 min. At 50° C., 11 g of 30% (w/w) aqueous sodium hydroxide solutionare slowly added dropwise to this suspension. A clear to slightly turbidsolution results. This solution is stirred for a bit longer and thenfiltered to give a clear solution.

The clear filtrate is slowly cooled to room temperature. Between 45 and30° C. crystallization, which can be accelerated by seeding with(−)-pantoprazole sodium, sets in. The resulting suspension is stirred atan internal temperature of <20° C. for another 2 h. The suspension isthen filtered, and the crystals are washed with 40 ml of MIBK.

Drying is carried out in a vacuum drying cabinet at <50 mbar and 40-45°C. [It is also possible to dispense with drying and to use the moistproduct (having an MIBK content of 10-20%) directly for step B]. Thewhite-beige crystalline product obtained after drying is hygroscopic.The water content is from 2 to 12%. The absorption and release of waterare reversible. Yield: 34 g=90% of theory (based on anhydrous product).Specific rotation: a_(D) ^(20°)=−95 (c=0.5, measured in methanol, sodiumsalt having a water content of 12%). m.p.: 145-165° C. (decomposition,sodium salt having a water content of 2%); 102-109° C. (decomposition,sodium salt having a water content of 12%).

B.2 (−)-Pantoprazole-Mg

30 g of (−)-pantoprazole sodium salt (calculated anhydrous substance)are suspended in 260 ml of water. The suspension is heated to 35-40° C.and stirred at 35-40° C. for another 10 min. This gives a clearsolution. The clear solution is cooled to 22-27° C. 14.3 g of magnesiumchloride hexahydrate are dissolved in 100 ml of water, and at roomtemperature and with stirring, the solution is slowly added dropwise tothe (−)-pantoprazole sodium salt solution. The resulting suspension isthen stirred at room temperature for another 4 h. The suspension is,under pressure, filtered through a Nutsche filter, and the product is, alittle at a time, washed twice with 300 ml of water. Drying in a vacuumdrying cabinet at <50 mbar and 40-45° C. gives 27.5 g (90%) of the titlecompound of m.p. 160-163° C. Water content 4.3-4.4%; specific rotation:a_(D) ^(20°)=−129 (c=0.5, measured in methanol).

C. Production of Dosage Forms According to the Invention Example C.1

Pellets made by Wurster coating (Nonpareilles):

I. Active Pellets:

a.) Sucrose starter pellets (0.425-0.5 mm) 500.0 g b.) Sodium carbonate30.0 g c.) (S)-Pantoprazole-Mg dihydrate 300.0 g d.)Polyvinylpyrrolidone K 25 35.0 ga. is sprayed with an aqueous dispersion of b., c. and d. in a fluidisedbed process (Wurster equipment) or other suitable equipments (e.g.coating pan).

II. Intermediate Layer (Subcoating):

e.) Hydroxypropylmethylcellulose 120.0 g f.) Titanium dioxide 2.0 g g.)LB Iron oxide yellow 0.2 g h.) Propylene glycol 24.0 ge. is dissolved in water (A). f. and g. are suspended in water using ahigh shear mixer (B). A and B are combined and after addition of h. theresulting suspension is sieved through a suitable sieve. The suspensionis sprayed onto 500 g of the active pellets obtained under I using afluidised bed process (Wurster) or other suitable processes (e.g.coating pan).III. Coating with a Layer which is Resistant to Gastric Juice (EntericCoating):

i.) Eudragit ®L 30 D 230.0 g j.) Triethyl citrate  7.0 gi. is suspended in water and after addition of j. the resultingdispersion is sieved through a suitable sieve. III is sprayed onto 500 gof the isolated pellets obtained under II in a Wurster fluidisedbed-apparatus or other suitable equipments (e.g. coating pan).

The resulting enteric coated pellets could be filled in hard gelatinecapsules of suitable size (e.g. size 2) or tableted using suitabletableting ingredients (e.g. microcrystalline cellulose or lactosemonohydrate) on a prevalent tablet press (see examples C6/7).

Example C.2

Pellets made by Wurster coating (Nonpareilles):

I. Active Pellets:

a.) Cellulose pellets (0.6-0.7 mm) 1000.0 g b.) Sodium carbonate 75.0 gc.) (S)-Pantoprazole-Mg dihydrate 650.0 g d.) Polyvinylpyrrolidone K 2580.0 ga. is sprayed with an aqueous dispersion of b., c. and d. in a fluidisedbed process (Wurster equipment) or other suitable equipments (e.g.coating pan).

II. Intermediate Layer (Subcoating):

e.) Hydroxypropylmethylcellulose 250.0 g f.) Titanium dioxide 5.0 g g.)LB Iron oxide yellow 0.45 ge. is dissolved in water (A). f. and g. are suspended in water using ahigh shear mixer (B). A and B are combined and the resulting suspensionis sieved through a suitable sieve. The suspension is sprayed onto 1000g of the active pellets obtained under I using a fluidised bed process(Wurster) or other suitable processes (e.g. coating pan).III. Coating with a Layer which is Resistant to Gastric Juice (EntericCoating):

h.) Eudragit ® L 30 D 365.0 g i.) Triethyl citrate  15.0 gh. is suspended in water and after addition of i. the resultingdispersion is sieved through a suitable sieve. III is sprayed onto 1000g of the isolated pellets obtained under II in a Wurster fluidisedbed-apparatus or other suitable equipments (e.g. coating pan).

The resulting enteric coated pellets could be filled in hard gelatinecapsules of suitable size (e.g. size 2) or tableted using suitabletableting ingredients (e.g. microcrystalline cellulose or lactosemonohydrate) on a prevalent tablet press (see examples C6/7).

Example C.3

Pellets made by Wurster coating (Nonpareilles):

I. Active Pellets:

a.) Cellulose pellets (0.4-0.5 mm) 2000.0 g b.) Sodium carbonate  136.0g c.) (S)-Pantoprazole-Mg dihydrate 1420.0 g d.) Polyvinylpyrrolidone K25  117.0 g e.) Sodium dodecylsulfate (SDS)  16.4 g

To produce core material, suspension layering is performed in a fluidbed apparatus or other suitable equipment as described in example C1.

II. Intermediate Layer (Subcoating):

f.) Hydroxypropylmethylcellulose 600.0 g  g.) Polyvinylpyrrolidone K 25 8.0 g h.) Titanium dioxide 10.0 g i.) LB Iron oxide yellow  1.0 g

The pellets covered with intermediate layer are produced as described inexample C1.

III. Coating with a Layer which is Resistant to Gastric Juice (EntericCoating):

j.) Hydroxypropylmethylcellulose acetate succinate 800.0 g k.) Triethylcitrate 250.0 g l.) Ethanol 7250.0 g 

The enteric coating layer is applied to the isolated pellets usingfluidized bed equipment from a water/ethanol solution.

The resulting enteric coated pellets could be filled in hard gelatinecapsules of suitable size (e.g. size 2) or tableted using suitabletableting ingredients (e.g. microcrystalline cellulose or lactosemonohydrate) on a prevalent tablet press (see examples C6/7).

Example C.4

Pellets made by extrusion/spheronization:

I. Manufacture of Pellets Using Extrusion/Spheronization:

a.) (S)-Pantoprazole-Mg dihydrate 250.0 g  b.) Microcrystallinecellulose 150.0 g  c.) Sodium starch glycolate 20.0 g d.) Sodiumcarbonate 32.5 g e.) Sodium carboxymethylcellulose 25.0 g f.)Polyvinylpyrrolidone K 25 35.0 ga.-c. are mixed using a suitable mixer. d.-f. are dissolved in water andthe resulting binder solution is added to the powder mixture. Afteraddition of the solution and mixing the mass is extruded using a screwextruder. Afterwards the granules are rounded using a spheronizer anddryed in a fluidised bed apparatus.

II. Intermediate Layer (Subcoating):

The application of the intermediate layer is carried out by a procedureanalogus to that described for the nonpareilles pellets (example C1 toC3) using fluidised bed or other suitable equipment.

III. Coating with a Layer which is Resistant to Gastric Juice:

The application of the gastric resistant layer is carried out by aprocedure analogus to that described for the nonpareilles pellets(example C1 to C3) using fluidised bed or other suitable equipment.

The resulting enteric coated pellets could be filled in hard gelatinecapsules of suitable size (e.g. size 2) or tableted using suitabletableting ingredients (e.g. microcrystalline cellulose or lactosemonohydrate) on a prevalent tablet press (see examples C6/7).

Example C.5

Pellets made by extrusion/spheronization:

I. Manufacture of Pellets Using Extrusion/Spheronization:

a.) (S)-Pantoprazole-Mg dihydrate 1300.0 g  b.) Microcrystallinecellulose 700.0 g c.) Lactose monohydrate 150.0 g d.)Hydroxypropylmethylcellulose 110.0 g e.) Sodium carbonate 180.0 g f.)Pregelatinized starch 125.0 g g.) Polyvinylpyrrolidone K 25 200.0 g

The extrusion pellets are produced as described in example C4.

II. Intermediate Layer (Subcoating):

The application of the intermediate layer is carried out by a procedureanalogus to that described for the nonpareilles pellets (example C1 toC3) using fluidised bed or other suitable equipment.

III. Coating with a Layer which is Resistant to Gastric Juice:

The application of the gastric resistant layer is carried out by aprocedure analogus to that described for the nonpareilles pellets(example C1 to C3) using fluidised bed or other suitable equipment.

The resulting enteric coated pellets could be filled in hard gelatinecapsules of suitable size (e.g. size 2) or tableted using suitabletableting ingredients (e.g. microcrystalline cellulose or lactosemonohydrate) on a prevalent tablet press (see examples C6/7).

Example C.6

Multiple unit tableted dosage form made from Nonpareilles-Pellets:

I. Active Pellets:

a.) Cellulose pellets (0.6-0.7 mm) 2500.0 g b.) Sodium carbonate  180.0g c.) (S)-Pantoprazole-Mg dihydrate 1700.0 g d.) Polyvinylpyrrolidone K25  250.0 g e.) Sodium dodecylsulfate  18.0 ga. is sprayed with an aqueous dispersion of b., c., d. and e. in afluidized bed process (Wurster equipment) or other suitable equipments(e.g. coating pan).

II. Intermediate Layer (Subcoating):

f.) Hydroxypropylmethylcellulose 600.0 g g.) Talcum (micronized) 100.0 gh.) Magnesium stearate  80.0 gf. is dissolved in water (A). g. and h. are suspended in water using ahigh shear mixer (B). A and B are combined and the resulting suspensionis sieved through a suitable sieve. The suspension is sprayed onto 2500g of the active pellets obtained under I using a fluidised bed process(Wurster) or other suitable processes (e.g. coating pan).III. Coating with a Layer which is Resistant to Gastric Juice (EntericCoating):

i.) Methacrylic acid copolymer 925.0 g j.) Polyethylene glycole 400 28.0 gi. is suspended in water and after addition of j. the resultingdispersion is sieved through a suitable sieve. III is sprayed onto 2500g of the isolated pellets obtained under II in a Wurster fluidisedbed-apparatus or other suitable equipments (e.g. coating pan).

IV. Tablets:

k.) Microcrystalline cellulose 3750.0 g l.) Crosslinkedpolyvinylpyrrolidone  100.0 g m.) Magnesium stearate   7.0 g

2500 g of enteric coated pellets are mixed with the tabletingexcinpients and compressed into tablets using a single punch tabletingmachine equipped with 11 mm round punches. The amount of pantoprazole isapprox. 20 mg.

Example C.7

Multiple unit tableted dosage form made from Extrusion-Pellets:

I. Manufacture of Pellets Using Extrusion/Spheronization:

a.) (S)-Pantoprazole-Mg dihydrate 433.0 g  b.) Microcrystallinecellulose 240.0 g  c.) Lactose monohydrate 55.0 g d.)Hydroxypropylmethylcellulose 35.0 g e.) Sodium carbonate 60.0 g f.)Sodium dodecylsulfate  5.5 g g.) Pregelatinized starch 35.0 g h.)Polyvinylpyrrolidone K 25 70.0 g

The extrusion pellets are produced as described in example C5.

II. Intermediate Layer (Subcoating):

i.) Hydroxypropylmethylcellulose 190.0 g  j.) Polyvinylpyrrolidone K 25 8.0 g j.) Talcum (micronized) 32.0 g k.) Magnesium stearate 14.0 g

The application of the intermediate layer is carried out by a procedureanalogus to that described for the nonpareilles pellets (example C1 toC3) using fluidised bed or other suitable equipment.

III. Coating with a Layer which is Resistant to Gastric Juice (EntericCoating):

l.) Methacrylic acid copolymer 296.0 g m.) Glycerol triacetate  28.0 g

The application of the gastric resistant layer is carried out by aprocedure analogus to that described for the nonpareilles pellets(example C1 to C3) using fluidised bed or other suitable equipment.

IV. Tablets:

n.) Microcrystalline cellulose 1200.0 g  o.) Crosslinkedpolyvinylpyrrolidone 32.0 g p.) Polyethyleneglycole 4000 38.0 g q.)Magnesium stearate  4.5 g

The enteric coated extrusion pellets are tableted with the abovetableting excipients as described in example C6 of an amount ofapproximately 40 mg pantoprazole.

Example C.8 Tablets: I. Tablet Core:

a.) (S)-Pantoprazole-Mg dihydrate 43.04 mg  b.) Sodium carbonate 5.55 mgc.) Mannitol 52.66 mg  d.) Crospovidone 40.00 mg  e.)Polyvinylpyrrolidone K 25 5.00 mg f.) Purified water 7.42 mg g.) Calciumstearate 3.00 mga. is dry-mixed with a part of b., a part of c. and d. and put in thevessel of a fluid bed granulator; e. is dissolved in f. together withthe other part of b. and c. to form the granulation liquid. The solutionis sprayed on the mixture under convenient conditions. After drying andmixing with g. the mixture is pressed into tablets using a rotarytableting machine equipped with 7 mm round punches. Tablet weight isapprox. 156.7 mg, corresponding to 40 mg pantoprazole (i.e. 43.04 mg(S)-pantoprazole-Mg dihydrate).

II. Intermediate Layer (Subcoating):

h.) Hydroxypropylmethylcellulose 11.87 mg  i.) Polyvinylpyrrolidone K 250.24 mg j.) Titanium dioxide 0.21 mg k.) LB Iron oxide yellow 0.02 mgl.) Propylene glycol 2.66 mgh. is dissolved in water (A). j. and k. are suspended in a solution ofi. in water using a high shear mixer (B). After sieving of B, A and Bare combined I. is added to the suspension. The suspension is sprayedonto the tablet cores obtained under I using a coating pan.III. Coating with a Layer which is Resistant to Gastric Juice (EntericCoating):

m.) Eudragit ® L 30 D 7.27 mg n.) Triethyl citrate 0.73 mgn. is suspended in water and mixed m. III is sprayed onto the isolatedtablets obtained under II using a coating pan.

Example C.9 Tablets: I. Tablet Core:

a.) (S)-Pantoprazole-Mg dihydrate 43.04 mg  b.) Sodium carbonate 5.55 mgc.) Mannitol 51.94 mg  d.) Crospovidone 40.00 mg  e.)Polyvinylpyrrolidone K 25 5.00 mg f.) Sodium dodecylsulfate 0.72 mg g.)Purified water 7.42 mg h.) Calcium stearate 3.00 mgf. and a part of b. are dissolved in water, a part of c. is added and a.is suspended in the solution. A solution of e. in water is added to thesuspension. The other part of b. and c. is mixed with d. and the mixtureis put in the vessel of a fluid bed granulator. The suspension issprayed on the mixture under convenient conditions. After drying andmixing with h. the mixture is compressed into tablets using a rotarytableting machine equipped with 7 mm round punches. Tablet weight isapprox. 156.7 mg.

The tablet cores are isolated and layered with an enteric coating asdescribed in Example C8.

Example C.10 Tablets: I. Tablet Core:

a.) (S)-Pantoprazole-Mg dihydrate 43.04 mg  b.) Sodium carbonate 5.55 mgc.) Mannitol 52.66 mg  d.) Crospovidone 40.00 mg  e.)Polyvinylpyrrolidone K 30 5.00 mg f.) Purified water 7.42 mg g.) Calciumstearate 3.00 mg

The tablet cores are produced as described in example C8.

The tablet cores are layered with an isolating coating and an entericcoating as described in example 08.

Example C.11 Tablets: I. Tablet Core:

a.) (S)-Pantoprazole-Mg dihydrate 43.04 mg  b.) Sodium carbonate 5.55 mgc.) Mannitol 52.66 mg  d.) Crospovidone 40.00 mg  e.)Polyvinylpyrrolidone K 17 5.00 mg f.) Purified water 7.42 mg g.) Calciumstearate 3.00 mg

The tablet cores are produced as described in example C8.

The tablet cores are layered with an isolating coating and an entericcoating as described in example C8.

Example C.12 Tablets: I. Tablet Core:

a.) (S)-Pantoprazole-Mg dihydrate 43.04 mg  b.) Sodium carbonate 5.55 mgc.) Mannitol 52.66 mg  d.) Crospovidone 40.00 mg  e.)Polyvinylpyrrolidone K 12 5.00 mg f.) Purified water 7.42 mg g.) Calciumstearate 3.00 mg

The tablet cores are produced as described in example C8.

The tablet cores are layered with an isolating coating and an entericcoating as described in example C8.

Example C.13 Tablets: I. Tablet Core:

a.) (S)-Pantoprazole-Mg dihydrate 43.04 mg  b.) Sodium carbonate 5.55 mgc.) Lactose 55.00 mg  d.) Crospovidone 35.00 mg  e.)Polyvinylpyrrolidone K 25 5.00 mg f.) Purified water 7.42 mg g.) Calciumstearate 3.00 mg

The tablet cores are produced as described in example C8. Tablet weightapprox. 154 mg.

II. Intermediate Layer (Subcoating):

h.) Hydroxypropylmethylcellulose 12.20 mg  i.) Titanium dioxide 0.21 mgj.) LB Iron oxide yellow 0.02 mgh. is dissolved in water (A). i. and j. are suspended in water using ahigh shear mixer (B). A and B are combined and the resulting suspensionis sieved through a suitable sieve. The suspension is sprayed onto thetablet cores obtained under I using a coating pan.

The isolated tablet cores are layered with an enteric coating asdescribed in example C8.

Example 0.14 Tablets: I. Tablet Core:

a.) (S)-Pantoprazole-Mg dihydrate 43.04 mg  b.) Trinatriumphosphate 5.55mg c.) Mannitol 55.00 mg  d.) Crospovidone 40.00 mg  e.)Polyvinylpyrrolidone K 25 5.00 mg f.) Purified water 7.42 mg g.)Magnesium stearate 3.00 mg

The tablet cores are produced as described in example C8. Tablet weightapprox. 159 mg.

II. Intermediate Layer (Subcoating):

The tablet cores are layered with an isolating coating as described inexample C8.

III. Coating with a Layer which is Resistant to Gastric Juice (EntericCoating):

m.) Methacrylic acid copolymer  6.5 mg n.) Glycerol triacetate 0.65 mg

The application of the gastric resistant layer is carried out asdescribed in example 08.

Example C.15

I. Tablet core

a) (S)-Pantoprazole-Mg dihydrate 43.04 mg b) Sodium carbonate  5.55 mgc) Mannitol 52.66 mg d) Crospovidone 40.00 mg e) PVP 90 (povidone)  5.00mg f) Calcium stearate  3.00 mga) is mixed with some of b), c) and the complete amount of d). Theremainders of b) and c) are added to a clear aqueous solution of e).Granules are obtained with this solution in a fluidized bed. f) is addedto the dry granules and the granules are pressed on a suitabletablet-press.

II. Preliminary Isolation (Intermediate Layer)

g) HPMC 2910, 3 cps 11.87 mg  h) PVP 25 0.24 mg i) Titanium dioxide 0.21mg j) Iron oxide yellow 100 E 172 0.02 mg k) Propylene glycol 2.66 mgTotal weight per preisolated core  172 mgg) is dissolved in water and h) is added and also dissolved (A). i) andj) are suspended in water using a suitable stirrer (B). A and B arecombined. After addition of k), the suspension is sieved immediatelybefore further processing, during which the tablet cores obtained underI. are coated to an adequate thickness of the intermediate layer in asuitable coating apparatus.III. Coating with a Layer which is Resistant to Gastric Juice

l) Eudragit L 30 D 7.27 mg m) Triethyl citrate 0.73 mg Total weight perfilm-coated tablet  180 mg resistant to gastric juicel) is diluted with water and m) is added. The dispersion is sievedbefore processing.

The preisolated tablets are sprayed in suitable coating apparatusesusing the obtained dispersion.

Example C.16

Pellets made by Wurster coating (Nonpareilles):

I. Active Pellets:

a.) Sucrose starter pellets (0.71-0.85 mm)  4.0 kg b.) Sodium carbonate0.27 kg c.) (S)-Pantoprazole-Mg dihydrate 2.84 kg d.)Polyvinylpyrrolidone K 25 0.23 kg e.) Pregelatinized starch 0.22 kg f.)Sodium dodecylsulfate 0.03 kga. is sprayed with an aqueous dispersion of the other ingredients in afluidised bed process (Wurster equipment) or other suitable equipments(e.g. coating pan).

II. Intermediate Layer (Subcoating):

g.) Hydroxypropylmethylcellulose 1.830 kg h.) Titanium dioxide 0.028 kgi.) LB Iron oxide yellow 0.003 kg j.) Polyvinylpyrrolidone K25 0.021 kgg. and j. are dissolved in water (A). h. and i. are suspended in waterusing a high shear mixer (B). A and B are combined and the resultingsuspension is sieved through a suitable sieve. The suspension is sprayedonto the active pellets obtained under I using a fluidised bed process(Wurster) or other suitable processes (e.g. coating pan).III. Coating with a Layer which is Resistant to Gastric Juice (EntericCoating):

k.) Eudragit ® L 30 D 4.40 kg l.) Triethyl citrate 0.13 kg m.) Talcum0.06 kgk. is suspended in water and after addition of I. the resultingdispersion is sieved through a suitable sieve. The dispersion is sprayedon the isolated pellets obtained under II in a Wurster fluidisedbed-apparatus or other suitable equipments (e.g. coating pan).

The resulting enteric coated pellets are mixed with talcum (m) and couldbe filled in hard gelatine capsules of suitable size (e.g. size 2) ortableted using suitable tableting ingredients (e.g. microcrystallinecellulose or lactose monohydrate) on a prevalent tablet press.

INDUSTRIAL APPLICABILITY

The dosage forms according to the invention containing the magnesiumsalt of (S)-pantoprazole can be employed for the treatment andprevention of all the diseases, which are regarded as treatable oravoidable by the use of pyridin-2-ylmethylsulfinyl-1H-benzimidazoles. Inparticular, such dosage forms according to the invention can be employedin the treatment of stomach disorders. Examples which may be mentionedin connection with the invention are the treatment or prophylaxis ofbenign gastric ulcer, gastro-oesophageal reflux disease,Zollinger-Ellison syndrome, duodenal ulcer, duodenal ulcer associatedwith Helicobacter pylori, prophylaxis of NSAID-associated gastric orduodenal ulcer in patients with an increased risk of gastroduodenalcomplication who require continued NSAID treatment or combinationtherapy with antibiotics in the eradication of Helicobacter pylori. Suchdosage forms according to the invention contain between 1 and 500 mg,preferably between 5 and 100 mg, particularly preferable between 5 and80 mg of the pantoprazole. Examples, which may be mentioned are tabletsor capsules which contains the (S)-pantoprazole magnesium salt in anamount corresponding to 10, 20, 40, 50, 80 or 100 mg of pantoprazole(free acid). The administration of the daily dose (e.g. 40 mg of activecompound) can be carried out, for example, in the form of an individualdose or by means of a number of doses of the administration formsaccording to the invention (e.g. 2 times 20 mg of active compound).

The invention therefore also relates to a method for the prophylaxis ortreatment of a clinical condition in a mammal, such as a human, forwhich a proton pump inhibitor is indicated, which comprisesadministration of a therapeutically effective amount (S)-pantoprazolemagnesium in a dosage form according to the invention. In one embodimentthe clinical condition is selected from the group of benign gastriculcer, gastro-oesophageal reflux disease, Zollinger-Ellison syndrome,duodenal ulcer, duodenal ulcer associated with Helicobacter pylori,prophylaxis of NSAID-associated gastric or duodenal ulcer in patientswith an increased risk of gastroduodenal complication who requirecontinued NSAID treatment and combination therapy with antibiotics inthe eradication of Helicobacter pylori. In a preferred embodiment theclinical condition is gastro-oesophageal reflux disease (GERD), inparticular GERD I to III (according to Savary/Miller classification,optionally modified according to Siewert).

The dosage forms according to the invention can be combined with othermedicaments, either in various combinations or in a fixed combination.In connection with the administration forms according to the invention,which contain magnesium salt of (S)-pantoprazole as active compounds,combinations with antimicrobial active compounds and combinations withNSAIDs (nonsteroidal antiinflammatory drugs) are particularly worthy ofmention. Combination with antimicrobial agents, such as are employed forthe control of the microorganism Helicobacter pylori (H. pylori), mayparticularly be mentioned.

Examples of suitable antimicrobial active compounds (active againstHelicobacter pylori) are described in EP-A-0 282 131. Examples ofantimicrobial agents suitable for the control of the microorganismHelicobacter pylori which may be mentioned are, for example, bismuthsalts [e.g. bismuth subcitrate, bismuth subsalicylate, ammoniumbismuth(III) potassium citrate dihydroxide, bismuth nitrate oxide,dibismuth tris(tetraoxodialuminate)], but in particular β-lactamantibiotics, for example penicillins (such as benzylpenicillin,phenoxymethylpenicillin, propicillin, azidocillin, dicloxacillin,flucloxacillin, oxacillin, amoxicillin, bacampicillin, ampicillin,mezlocillin, piperacillin or azlocillin), cephalosporins (such ascefadroxil, cefaclor, cefalexin, cefixime, cefuroxime, cefetamet,cefadroxil, ceftibuten, cefpodoxime, cefotetan, cefazolin, cefoperazon,ceftizoxime, cefotaxime, ceftazidime, cefamandol, cefepime, cefoxitin,cefodizime, cefsulodin, ceftriaxon, cefotiam or cefinenoxime) or otherβ-lactam antibiotics (e.g. aztreonam, loracarbef or meropenem); enzymeinhibitors, for example sulbactam; tetracyclines, for exampletetracycline, oxytetracycline, minocycline or doxycycline;aminoglycosides, for example tobramycin, gentamicin, neomycin,streptomycin, amikacin, netilmicin, paromomycin or spectinomycin;amphenicols, for example chloramphenicol or thiamphenicol; lincomycinsand macrolide antibiotics, for example clindamycin, lincomycin,erythromycin, clarithromycin, spiramycin, roxithromycin or azithromycin;polypeptide antibiotics, for example colistin, polymixin B, teicoplaninor vancomycin; gyrase inhibitors, for example norfloxacin, cinoxacin,ciprofloxacin, pipemidic acid, enoxacin, nalidixic acid, pefloxacin,fleroxacin or ofloxacin; nitroimidazoles, for example metronidazole; orother antibiotics, for example fosfomycin or fusidic acid. Particularlyworthy of mention in this connection is the administration of themagnesium salt of pantoprazole with the combination of a multiplicity ofantimicrobial active compounds, for example with the combination of abismuth salt and/or tetracyclines with metronidazole or the combinationof amoxicillin or clarithromycin with metronidazole and amoxicillin withclarithromycin.

1.-37. (canceled)
 38. A dosage form for oral administration of(S)-pantoprazole magnesium dihydrate salt comprising a therapeuticallyeffective amount of the (S)-pantoprazole magnesium dihydrate salttogether with low molecular weight polyvinylpyrrolidone as a binder andone or more other suitable pharmaceutically acceptable excipients. 39.The dosage form according to claim 38, which is a solid dosage form intablet or pellet form.
 40. The dosage form according to claim 38, whichis a delayed release dosage form comprising an enteric layer, which issoluble in neutral or alkaline conditions and at least one intermediatelayer.
 41. The dosage form according to claim 38, which is an orallyadministerable medicament in pellet or tablet form which is resistant togastric juice, and in which each pellet or tablet comprises a core inwhich (S)-pantoprazole magnesium dihydrate is in admixture with lowmolecular weight polyvinylpyrrolidone as a binder and a filler and,optionally comprises, a member selected from the group consisting ofanother tablet auxiliary, a basic physiologically-tolerated inorganiccompound, an inert water-soluble intermediate layer surrounding the coreand an outer layer which is resistant to gastric juice.
 42. The dosageform according to claim 41 in tablet form, wherein mannitol is thefiller.
 43. The dosage form according to claim 41, wherein apharmacologically tolerated alkali metal, alkaline earth metal or earthmetal salt of a weak acid or pharmacologically tolerated hydroxide oroxide of an alkaline earth or earth metal is the basic, physiologicallytolerated inorganic compound.
 44. The dosage form according to claim 43,wherein sodium carbonate is the basic, physiologically toleratedinorganic compound.
 45. The dosage form according to claim 38, whereinthe low molecular weight polyvinylpyrrolidone has an average molecularweight below 70,000.
 46. The dosage form according to claim 38 whereinthe low molecular weight polyvinylpyrrolidone has an average molecularweight below 60,000.
 47. The dosage form according to claim 38, whereinthe low molecular weight polyvinylpyrrolidone has an average molecularweight below 40,000.
 48. The dosage form according to claim 38,comprising the (S)-pantoprazole magnesium dihydrate salt together withlow molecular weight polyvinylpyrrolidone in an alkaline pellet ortablet core.
 49. The dosage form according to claim 48, comprising atleast one subcoating and an outer enteric layer, which is soluble in thesmall intestine.
 50. The dosage form according to claim 38, in tabletform, comprising as excipients for the tablet core sodium carbonate,mannitol, crospovidone, polyvinylpyrrolidone, and magnesium stearate.51. The dosage form according to claim 38, in tablet form, comprising asexcipients for the tablet core sodium carbonate, mannitol, crospovidone,polyvinylpyrrolidone, and calcium stearate.
 52. An oral dosage form inpellet or tablet form for magnesium dihydrate salt of (S)-pantoprazolecomprising a therapeutically effective amount of the magnesium dihydratesalt of (S)-pantoprazole together with low molecular weightpolyvinylpyrrolidone as a binder and one or more other pharmaceuticalexcipients in an alkaline pellet or tablet core, at least one subcoatingand an outer enteric layer which is soluble in the small intestine. 53.The dosage form according to claim 38 containing between 5 and 100 mg ofthe magnesium dihydrate salt of (S)-pantoprazole.
 54. The dosage formaccording to claim 53, which contains an amount of the magnesiumdihydrate salt of (S)-pantoprazole which corresponds to 10, 20, 40, 50,80 or 100 mg of (S)-pantoprazole.
 55. The dosage form according to claim54, which contains an amount of the magnesium dihydrate salt of(S)-pantoprazole which corresponds to 80 mg of (S)-pantoprazole.
 56. Thedosage form according to claim 38 in tablet form comprising a tabletcore, an intermediate layer and an enteric coating, wherein the tabletcore comprises (S)-pantoprazole magnesium dihydrate, sodium carbonate,mannitol, crospovidone, PVP 90 and calcium stearate, the intermediatelayer is formed of HPMC, PVP 25, Titanium dioxide, iron oxide yellow andpropylene glycol, and the enteric coating is formed of a methacrylicacid/methyl methacrylate copolymer and triethyl citrate.
 57. A methodfor the prophylaxis or treatment of a clinical condition in a mammal,such as a human, for which a proton pump inhibitor is indicated, whichcomprises administration of a therapeutically effective amount(S)-pantoprazole magnesium in a dosage form according to claim
 38. 58.The method of treatment according to claim 57, wherein the clinicalcondition is selected from the group consisting of benign gastric ulcer,gastro-oesophageal reflux disease, Zollinger-Ellison syndrome, duodenalulcer, duodenal ulcer associated with Helicobacter pylori, andprophylaxis of NSAID-associated gastric or duodenal ulcer in patientswith an increased risk of gastroduodenal complication who requirecontinued NSAID treatment and combination therapy with antibiotics inthe eradication of Helicobacter pylori.
 59. The method according toclaim 58, wherein the clinical condition is gastro-oesophageal refluxdisease (GERD).
 60. The method according to claim 59, wherein theclinical condition is GERD I to III according to Savary/MillerClassification.
 61. The method according to claim 59 wherein the dosageform is an oral dosage form in pellet form, comprising a pellet core anintermediate layer and an enteric coating, wherein the pellet core isformed from sucrose starter pellets, (S)-pantoprazole magnesiumdihydrate, sodium carbonate, PVP 25, pregelatinized starch and sodiumdodecylsulfate, the intermediate layer is formed of HPMC, PVP 25,titanium dioxide and iron oxide yellow, and the enteric coating isformed of Eudragit L 30 D and triethyl citrate.
 62. The method accordingto claim 57, wherein the effective amount of (S)-pantoprazole magnesiumcorresponds to 40 or 80 mg pantoprazole.
 63. The method according toclaim 62, wherein the treatment is a once daily treatment.
 64. Themethod for production of a dosage form according to claim 38 in pelletform by spraying a suspension of the magnesium salt of (S)-pantoprazole,starch and optionally other excipients in an aqueous solution of PVP onstarter pellets, drying the pellets, and layering them with subcoatingand enteric coating.
 65. The method for production according to claim64, wherein the starch is pregelatinized starch.
 66. The method forproduction of a dosage form according to claim 38 in pellet form byspraying a suspension of the magnesium salt of (S)-pantoprazole, sodiumcarbonate, pregelatinized starch and sodium dodecylsulfate in an aqueoussolution of PVP on starter pellets, drying the pellets, layering themwith subcoating and enteric coating, mixing with glidants whereapplicable and filling into capsules.
 67. A method for the prophylaxisor treatment of a clinical condition in a mammal, such as a human, forwhich a proton pump inhibitor is indicated, which comprisesadministration of a therapeutically effective amount (S)-pantoprazolemagnesium in a dosage form according to claim 52.